Uses for Piperacillin Sodium and Tazobactam Sodium

Gynecologic and Obstetric Infections

Treatment of postpartum endometritis or pelvic inflammatory disease (PID) caused by β-lactamase-producing Escherichia coli resistant to piperacillin but susceptible to piperacillin and tazobactam.121333435

Intra-abdominal Infections

Treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase-producing E. coli resistant to piperacillin but susceptible to piperacillin and tazobactam or caused by Bacteroides fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus.11213143335

For empiric treatment of CAP in adults with risk factors for Pseudomonas aeruginosa, IDSA and ATS recommend a combination regimen that includes an antipneumococcal, antipseudomonal β-lactam (piperacillin and tazobactam, cefepime, imipenem, meropenem) and ciprofloxacin or levofloxacin; one of these β-lactams, an aminoglycoside, and azithromycin; or one of these β-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone.41 If Ps. aeruginosa has been identified by appropriate microbiologic testing, these experts recommend treatment with a regimen that includes an antipseudomonal β-lactam (cefepime, ceftazidime, aztreonam, imipenem, meropenem, piperacillin, ticarcillin) and ciprofloxacin, levofloxacin, or an aminoglycoside.41

Treatment of moderate to severe nosocomial pneumonia caused by β-lactamase-producing S. aureus resistant to piperacillin but susceptible to piperacillin and tazobactam or caused by Acinetobacter baumanii, H. influenzae, Klebsiella pneumoniae, or Ps. aeruginosa resistant to piperacillin but susceptible to piperacillin and tazobactam.1333435 For nosocomial pneumonia caused by Ps. aeruginosa, used in conjunction with an aminoglycoside or fluoroquinolone with antipseudomonal activity (e.g., ciprofloxacin, levofloxacin).1333435

For initial empiric treatment of hospital-acquired pneumonia, ventilator-associated pneumonia, or health-care associated pneumonia in adults who are severely ill or have late-onset disease or risk factors for multidrug-resistant bacteria, ATS, IDSA, and other clinicians recommend an antipseudomonal cephalosporin (cefepime, ceftazidime), antipseudomonal penicillin (piperacillin and tazobactam, ticarcillin and clavulanate), or an antipseudomonal carbapenem (imipenem, meropenem) used in conjunction with an aminoglycoside (amikacin, gentamicin, tobramycin) or antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin).3442 In hospitals where oxacillin-resistant (methicillin-resistant) Staphylococcus is common or if there are risk factors for these strains, the initial regimen also should include vancomycin or linezolid.3442

Septicemia

Treatment of septicemia† caused by susceptible gram-negative bacteria. For initial empiric treatment of life-threatening sepsis, used in conjunction with vancomycin with or without an aminoglycoside.34

Piperacillin Sodium and Tazobactam Sodium Dosage and Administration

Administration

IV Administration

Piperacillin and tazobactam should not be admixed with other drugs (e.g., in a syringe or infusion bottle) and should not be added to blood products or albumin hydrolysates.13335

If concomitant use of an aminoglycoside is indicated (e.g., for treatment of nosocomial pneumonia), piperacillin and tazobactam and the aminoglycoside should be administered separately.13335

In certain situations when simultaneous coadministration of piperacillin and tazobactam and an aminoglycoside via Y-site infusion is considered necessary, this can be accomplished using only certain dosages of amikacin or gentamicin, only certain formulations of piperacillin and tazobactam (Zosyn) containing edetate disodium dihydrate (EDTA), and only certain acceptable diluents.13335 (See Tables.) For Y-site coadministration, do not use any formulations of piperacillin and tazobactam other than those specified in the tables and do not use tobramycin or any aminoglycoside other than amikacin or gentamicin.13335 Coadministration via Y-site infusion in any manner other than that specified in the tables may result in inactivation of the aminoglycoside.13335

Based on amikacin dosage of 10–15 mg/kg daily given in 2 divided doses or gentamicin dosage of 3–5 mg/kg daily given in 3 divided doses; higher dosage or once-daily dosage has not been evaluated for Y-site compatibility.

Based on amikacin dosage of 10–15 mg/kg daily given in 2 divided doses or gentamicin dosage of 3–5 mg/kg daily given in 3 divided doses; higher dosage or once-daily dosage has not been evaluated for Y-site compatibility.

Frozen Zosyn injections in Galaxy containers that contain 3.375 g/50 mL are not compatible with gentamicin and should not be used for Y-site coadministration with gentamicin.

Reconstitution and Dilution

Reconstitute Zosyn single-dose vials containing 2 g of piperacillin and 0.25 g of tazobactam, 3 g of piperacillin and 0.375 g of tazobactam, or 4 g of piperacillin and 0.5 g of tazobactam by adding 10, 15, or 20 mL, respectively, of 0.9% sodium chloride injection, sterile water for injection, 5% dextrose injection, bacteriostatic water for injection (with parabens or benzyl alcohol), or bacteriostatic sodium chloride injection (with parabens or benzyl alcohol).1 Shake thoroughly until contents are dissolved.1 Reconstituted solutions should be diluted further to the desired volume (usually 50–150 mL) with 0.9% sodium chloride injection, sterile water for injection (maximum recommended volume is 50 mL), 5% dextrose injection, or 6% dextrose in 0.9% sodium chloride.133 Lactated Ringer's injection is compatible with and can be used to dilute reconstituted solutions of Zosyn (with EDTA), but cannot be used to dilute piperacillin and tazobactam preparations that do not contain EDTA.133

ADD-Vantage vials containing Zosyn should be diluted according to the manufacturer’s labeling.1

Reconstitute Zosyn pharmacy bulk vials containing 36 g of piperacillin and 4.5 g of tazobactam by adding 152 mL of a compatible IV solution (see Solution Compatibility under Stability) to provide a solution containing 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.33 Pharmacy bulk vials of the drug are not intended for direct IV infusion; prior to administration, solutions reconstituted in the pharmacy bulk vial must be further diluted with a compatible IV solution.33

Thaw the commercially available injection (frozen) of Zosyn in Galaxy containers at room temperature (20–25°C) or in a refrigerator (2–8°C); do not force thaw by immersion in a water bath or by exposure to microwave radiation.35 A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature.35 Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact.35 Additives should not be introduced into the injection.35 The injections should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.35

Rate of Administration

Dosage

Available as a fixed combination of piperacillin sodium and tazobactam sodium in an 8:1 ratio; dosage usually expressed in terms of the total of the piperacillin and tazobactam content of the fixed combination (i.e., grams of Zosyn).13335 Potency of both piperacillin sodium and tazobactam sodium are expressed in terms of the bases.13335

Pediatric Patients

Intra-abdominal Infections

Appendicitis and/or Peritonitis

IV

Children 2 months to <9 months of age: 80 mg/kg of piperacillin and 10 mg/kg of tazobactam every 8 hours.13335

IV

Children ≥9 months of age weighing ≤40 kg: 100 mg/kg of piperacillin and 12.5 mg/kg of tazobactam every 8 hours.13335

Respiratory Tract Infections

IV

Nosocomial Pneumonia

IV

4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours for 7–14 days; used in conjunction with an aminoglycoside.13335

The aminoglycoside should be continued for the duration of treatment in patients in whom Ps. aeruginosa is isolated; if nosocomial pneumonia is not caused by Ps. aeruginosa, the aminoglycoside may be discontinued at the discretion of the clinician, taking into account severity of the infection and the patient’s clinical and bacteriologic progress.13335

Skin and Skin Structure Infections

IV

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with hepatic impairment.13123335

Serum half-lives of piperacillin and tazobactam are prolonged in patients with hepatic cirrhosis;133335 not considered clinically important.13123335

Renal Impairment

Dosage adjustment recommended in adults with Clcr ≤40 mL/minute and in adults undergoing hemodialysis or CAPD.17123335 No dosage recommendations for pediatric patients with renal impairment.13335

In adults with nosocomial pneumonia and renal impairment who are receiving concomitant aminoglycoside therapy, dosage of the aminoglycoside should be adjusted according to the recommendations for that drug.13335

Table 3. Dosage for Adults with Renal Impairment13335

Clcr (mL/min)

Daily Dosage (Except Nosocomial Pneumonia)

Daily Dosage (Nosocomial Pneumonia)

20–40

2.25 g every 6 hours

3.375 g every 6 hours

<20

2.25 g every 8 hours

2.25 g every 6 hours

Hemodialysis Patients

2.25 g every 12 hours; also give 0.75 g after each hemodialysis session

2.25 g every 8 hours; also give 0.75 g after each hemodialysis session

CAPD Patients

2.25 g every 12 hours

2.25 g every 8 hours

Cautions for Piperacillin Sodium and Tazobactam Sodium

Contraindications

Hypersensitivity to any penicillin, cephalosporin, or β-lactamase inhibitor.13335

Warnings/Precautions

Warnings

Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.133353637383940C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including piperacillin and tazobactam, and may range in severity from mild diarrhea to fatal colitis.133353637383940 Hyper toxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.13335

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.133353637383940 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.133353637383940

If CDAD is suspected or confirmed, piperacillin and tazobactam may need to be discontinued.133353637383940 Some mild cases may respond to discontinuance alone.3637383940 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.133353637383940

Sensitivity Reactions

Hypersensitivity Reactions

Prior to initiation of therapy, make careful inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.13335 Partial cross-allergenicity occurs among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.13335

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of piperacillin and tazobactam and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.13335

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.13335 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.13335

Hematologic Effects

Bleeding manifestation reported with some β-lactam antibiotics, including piperacillin.13335 These reactions have sometimes been associated with abnormal coagulation tests (e.g., clotting time, platelet aggregation, PT) and are most likely to occur in patients with renal failure.13335

Determine electrolyte concentrations periodically in patients with low potassium reserves; consider possibility of hypokalemia in those with potentially low potassium reserves who are receiving cytotoxic therapy or diuretics.13335

Cystic Fibrosis Patients

Laboratory Monitoring

Periodically assess organ system functions, including renal, hepatic, and hematopoietic, during prolonged therapy.2 Monitoring hematopoietic function is especially important when duration is ≥21 days (see Hematologic Effects under Cautions).13335

Specific Populations

Pregnancy

Lactation

Piperacillin distributed into milk; not known whether tazobactam is distributed into milk.13335 Use with caution.13335

Pediatric Use

Use for treatment of appendicitis and/or peritonitis in pediatric patients ≥2 months of age is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and pediatric patients.13335

Safety and efficacy not established in pediatric patients <2 months of age.13335

Geriatric Use

Piperacillin and tazobactam contains sodium (see Sodium Content and Electrolyte Imbalance under Cautions).13335 Patients receiving the usual IV dosage will receive 768 or 1024 mg (33.5 or 44.6 mEq) of sodium daily.133 Geriatric patients may respond to salt loading with blunted natriuresis;13335 this may be clinically important with regard to such diseases as congestive heart failure.13335

Select dosage with caution (usually starting at low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.13335

Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function.13335 Assess renal function periodically since geriatric patients are more likely to have renal impairment.13335

No dosage adjustments except those related to renal function.13335 (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Serum half-lives of piperacillin and tazobactam are prolonged in patients with hepatic cirrhosis;133335 not considered clinically important.13123335

No dosage adjustment required in patients with hepatic impairment.13123335

Renal Impairment

Dosage adjustments recommended in adults with Clcr ≤40 mL/minute and in those undergoing hemodialysis or CAPD.13335 No dosage recommendations in pediatric patients with impaired renal function.13335 (See Renal Impairment under Dosage and Administration.)

Interactions for Piperacillin Sodium and Tazobactam Sodium

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Aminoglycosides

Substantial inactivation of aminoglycosides can occur if combined with piperacillin in vitro13335

Amikacin and gentamicin: Compatible in vitro with formulations of piperacillin and tazobactam (Zosyn) containing EDTA and can be used for simultaneous Y-site administration under specific conditions13335 (see Administration under Dosage and Administration)

Tobramycin: Not compatible in vitro with piperacillin and tazobactam, including formulations of Zosyn containing EDTA13335

Studies using piperacillin indicate clinically important decreases in aminoglycoside concentrations if the drugs are administered concomitantly in patients with end-stage renal disease (ESRD) requiring hemodialysis; effect may vary depending on the specific aminoglycoside13335

Tobramycin: Sequential administration of Zosyn and tobramycin in patients with normal or mild to moderate renal impairment does not appear to significantly affect tobramycin pharmacokinetics, but tobramycin concentrations may be significantly altered in those with ESRD requiring hemodialysis 13335

If simultaneous coadministration of piperacillin and tazobactam and an aminoglycoside via Y-site infusion is considered necessary, use only certain dosages of amikacin or gentamicin, only certain formulations of piperacillin and tazobactam (Zosyn) containing EDTA, and only certain acceptable diluents13335 (see Administration under Dosage and Administration)

Anticoagulants (oral anticoagulant, heparin)

Monitor coagulation parameters more frequently if used concomitantly with high doses of heparin, oral anticoagulants, or other drugs that affect blood coagulation or thrombocyte function13335

Half-life

Plasma half-live of piperacillin and of tazobactam range from 0.7–1.2 hours.13335

Special Populations

Patients with cirrhosis: Half-life of piperacillin and tazobactam increased by approximately 25 and 18%, respectively, compared with patients with normal hepatic function.13335

Patients with renal impairment: Half-lives of piperacillin and tazobactam increase with decreasing Clcr.13335 In those with Clcr <20 mL/minute, half-life of piperacillin is 2 times higher and half-life of tazobactam is 4 times higher compared with patients with normal renal function.13335

Pediatric patients: Clearance of piperacillin and tazobactam in children 9 months to 12 years of age is comparable to that reported in adults.13335 Piperacillin clearance in children 2–9 months of age is estimated to be 80% of that value;13335 clearance is slower in patients <2 months of age compared to older children.13335

Stability

Storage

Parenteral

Powder for Injection

Reconstituted single-dose vials should be used immediately after reconstitution; any unused injection should be discarded after 24 hours if stored at 20–25°C or after 48 hours if refrigerated at 2–8°C.1

ADD-Vantage vials prepared using 0.9% sodium chloride or 5% dextrose are stable for 24 hours at room temperature; these reconstituted solutions should not be refrigerated or frozen.1

Reconstituted bulk vials should be discarded after 24 hours if stored at 20–25°C or after 48 hours if refrigerated at 2–8°C.33 Do not freeze.33

Injection (Frozen)

-20° C or lower.35 Thawed solutions of the commercial frozen injection are stable for 24 hours at room temperature (20–25°C) or 14 days at 2–8°C.35

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Solution Compatibility

If sterile water for injection is used for dilution, the maximum recommended volume is 50 mL.133

Lactated Ringer’s injection is compatible with Zosyn (with EDTA), but is incompatible with and should not be used to reconstitute or dilute piperacillin and tazobactam preparations that do not contain EDTA.133

Chemically unstable in solutions containing only sodium bicarbonate and solutions that alter pH.13335

Actions and Spectrum

Piperacillin and tazobactam commercially available in the US (Zosyn) is formulated with EDTA and sodium citrate 1333544 to decrease certain aspects of chemical degradation and particulate formation and to facilitate coadministration with certain aminoglycosides.44 (See Dosage and Administration.)

Anaerobes: Active in vitro and in clinical infections against Bacteroides fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus.13335 Also active in vitro against B. distasonis and Prevotella melaninogenica.13335

Advice to Patients

Advise patients that antibacterials (including piperacillin and tazobactam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).13335

Importance of completing full course of therapy, even if feeling better after a few days.13335

Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with piperacillin and tazobactam or other antibacterials in the future.13335

Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.13335 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.13335

Importance of discontinuing therapy and informing clinician if an allergic reaction occurs.a

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

60 mg of (of piperacillin) per mL (3 g) and 7.5 mg (of tazobactam) per mL (0.375 g) (labeled as a combined total potency of 3.375 g) in 0.7% Dextrose

Zosyn Iso-osmotic in Dextrose Injection (Galaxy [Baxter])

Wyeth

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.